E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Triple negative Breast Cancer |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10075566 |
E.1.2 | Term | Triple negative breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
For BRCAm, Non BRCAm HRRm, Non HRRm subject population
- To assess the efficacy of the combination of Ceralasertib+Olaparib and the combination of AZD1775+Olaparib compared with olaparib monotherapy by assessment of PFS |
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E.2.2 | Secondary objectives of the trial |
-To assess the efficacy of combination of Ceralasertib+Olaparib and combination of AZD1775+Olaparib compared with olaparib monotherapy by assessment of PFS for HRRm and All subject populations
-To assess the efficacy of combination of Ceralasertib+Olaparib and combination of AZD1775+Olaparib compared with olaparib monotherapy in terms of ORR, DOR, tumour change and OS
- To compare the efficacy of combination of Ceralasertib+Olaparib with combination of AZD1775+Olaparib in terms of PFS, ORR, DOR, tumour change and OS
-To explore the frequency of and describe the nature of tumour HRR (including BRCA) mutation(s) in tumour samples and to compare this with germline HRR (including BRCA) mutation status
-To assess exposure to olaparib, Ceralasertib and AZD1775 in all patients
-To assess the safety and tolerability of combination of Ceralasertib+Olaparib and combination of AZD1775+Olaparib compared with olaparib monotherapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provision of informed consent prior to any study specific procedures
2. Patients must be male or female ≥18 years of age
3. Progressive cancer at the time of study entry
4. Histologically or cytologically confirmed TNBC at initial diagnosis with
evidence of metastatic or incurable advanced locoregional disease
(defined as ER and PgR negative [IHC nuclear staining <1% positive]
and HER2 negative [IHC 0, 1+ or IHC 2+ with corresponding ISH nonamplified
of ratio less than 2.0 or ISH non-amplified ratio less than 2.0]
as per ASCO-CAP HER2 guideline recommendations 2013 (ASCO-CAP).
Note: An Allred score of 0-2 is acceptable however for a score of 2 the
Proportion score must be checked to make sure it is 1 (≤1% cells are ER
positive)
5. Patients must have received at least 1 and no more than 2 prior lines
of treatment for metastatic or incurable advanced locoregional disease
with an anthracycline (doxorubicin, epirubicin) and/or a taxane (eg,
paclitaxel, docetaxel) unless contraindicated, in either the neo-adjuvant,
adjuvant or metastatic setting
Patients who have received platinum (cisplatin or carboplatin, either
as monotherapy or in combination) for advanced breast cancer are
eligible to enter the study provided there has been no evidence of
disease progression during the platinum chemotherapy
Patients who have received prior platinum based chemotherapy are
eligible if platinum was given either as potentially curative treatment for
a prior non breast cancer (ovarian cancer) with no evidence of disease
for ≥5 years prior to study entry or as adjuvant/neoadjuvant treatment
for breast cancer provided at least 12 months have elapsed between the
last dose of platinum-based treatment and randomisation
6. Confirmed presence of qualifying HRR mutation or absence of any HRR
mutation in tumour tissue by the Lynparza HRR assay
- FFPE tumour tissue blocks are required for each patient, but if not
available, tissue sections are accepted. At least twenty (thirty
preferable) unstained sections without cover slips must be submitted to
ensure sufficient material for the prospective Lynparza HRR testing to
determine study eligibility and research that will aid understanding of
the patient population relative to treatment with DDR and other cancer
agents
- If a patient has a previously known qualifying BRCA1/2 mutation or
other HRR mutation, then the patient can be invited to consent to the full
study. The patient will need to consent to provide an archival tumour
block or tissue sections for central assessment of the HRR mutation
status
7. At least one measurable lesion that can be accurately assessed at
baseline by computed tomography (CT) (magnetic resonance imaging
[MRI] where CT is contraindicated) and is suitable for repeated
assessment as per RECIST 1.1
8. Patients must have normal organ and bone marrow function measured
within 28 days prior to randomisation as defined below:
a) Haemoglobin ≥10.0 g/dL with no blood transfusions (packed red
blood cells) in the past 28 days
b) Absolute neutrophil count ≥ 1.5 x 109 /L
c) Platelet count ≥100 x 109 /L with no platelet transfusions in the past
28 days
d) Total bilirubin ≤1.5 x institutional upper limit of normal unless the
patient has documented Gilbert's Syndrome
e) Aspartate aminotransferase /alanine aminotransferase ≤2.5 x
institutional ULN unless liver metastases are present in which case they
must be ≤5 x ULN
f) Patients must have creatinine clearance of ≥51 mL/min estimated or
measured using standard methodology at the investigating centre
(Cockcroft-Gault, MDRD, CK-EPI, EDTA or 24 hr urine):
Estimated CrCl = (140-age [years]) x weight (kg) (x F) / serum
creatinine (mg/dL) x 72
where F=0.85 for females and F=1 for males
9. ECOG PS 0-1 within 28 days of randomisation
10. Postmenopausal or evidence of non childbearing status for women of
childbearing potential: negative urine or serum pregnancy test within 28
days of study treatment and confirmed prior to treatment on Day 1
Postmenopausal is defined as:
- Amenorrheic for 1 year or more following cessation of exogenous
hormonal treatments
- Luteinizing hormone and Follicle stimulating hormone levels in the
postmenopausal range for women under 50
- radiation-induced oophorectomy with last menses >1 year ago
- chemotherapy-induced menopause with >1 year interval since last
menses
- surgical sterilisation (bilateral oophorectomy or hysterectomy)
11. Women of childbearing potential and their partners, who are sexually
active, must agree to the use of 2 highly effective forms of contraception
in combination from the signing of the informed consent, throughout the
period of taking study treatment and for at least 1 month after last dose
of study drug(s)
Please see protocol for further details |
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E.4 | Principal exclusion criteria |
1.Involvement in the planning and/or conduct of the study (applies to
AstraZeneca staff and/or staff at the study site)
2.Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy
within 21 days of Cycle 1 Day 1 is not permitted. Palliative radiotherapy
must have been completed 21 or more days before Cycle 1 Day 1. The
patient can receive a stable dose of bisphosphonates or denosumab for
bone metastases, before and during the study as long as these were
started at least 5 days prior to study treatment
3.More than 2 prior lines of cytotoxic chemotherapy for metastatic
disease
- Prior treatments with hormonal therapy and non hormonal targeted
therapy are allowed and not counted as a prior line of cytotoxic
chemotherapy
- For the purposes of this protocol, the combination of an aromatase
inhibitor and everolimus is not considered cytotoxic chemotherapy
- Treatment with biologics will not be considered as prior line of therapy
4. Previous randomisation in the present study
5. Previous treatment with a PARP inhibitor (including olaparib) or other
DDR inhibitor (unless treatment was for less than 3 weeks duration and
at least 12 months have elapsed between the last dose and
randomisation. Patients that did not tolerate prior treatment are
excluded)
6. Exposure to a small molecule IP within 30 days or 5 half-lives
(whichever is longer) prior to randomisation. The minimum washout
period for immunotherapy shall be 42 days
7. Patients with MDS/AML or with features suggestive of MDS/AML
8. Patients with second primary cancer, EXCEPTIONS: adequately treated
non melanoma skin cancer, curatively treated in-situ cancer of the
cervix, Ductal Carcinoma in Situ (DCIS), stage 1 grade 1 endometrial
carcinoma, or other solid tumours curatively treated with no evidence of
disease for ≥ 5 years prior to study entry (including lymphomas [without
bone marrow involvement])
9. Mean resting corrected QTc interval using the Fridericia formula
(QTcF) >470 msec/female patients and >450 msec for male patients (as
calculated per institutional standards) obtained from 3 ECGs performed
2-5 minutes apart at study entry, or congenital long QT syndrome
No longer applicable from CSPv6.0 AZD1775 should not be given to
patients who have a history of Torsades de pointes unless all risk factors
that contributed to Torsades have been corrected. AZD1775 has not been
studied in patients with ventricular arrhythmias or recent myocardial
infarction
10. Any of the following cardiac diseases currently or within the last 6
months
- Unstable angina pectoris
- Congestive heart failure ≥ Class 2 as defined by the New York Heart
Association
- Acute myocardial infarction
- Conduction abnormality not controlled with pacemaker or medication
(patients with a conduction abnormality controlled with pacemaker or
medication at the time of screening are eligible)
- Significant ventricular or supraventricular arrhythmias (patients with
chronic rate-controlled atrial fibrillation in the absence of other cardiac
abnormalities are eligible)
11. Concomitant use of known strong cytochrome P (CYP) 3A inhibitors
(eg. itraconazole, telithromycin, clarithromycin, protease inhibitors
boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir,
boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin,
erythromycin, diltiazem, fluconazole, verapamil). The required washout
period prior to starting study treatment is 2 weeks
NAP from CSPv7.0 - Patient has had prescription or non-prescription drugs or other products
known to be sensitive CYP3A4 substrates or CYP3A4 substrates with a
narrow therapeutic index, or to be moderate to strong
inhibitors/inducers of CYP3A4 which cannot be discontinued 2 weeks
prior to Day 1 of dosing and withheld throughout the study until 2 weeks
after the last dose of study drug
NAP from CSPv7.0 - Transporter studies (in vitro) have shown that AZD1775 is an inhibitor of
breast cancer resistance protein (BCRP) Patients should stop using
herbal medications 7 days prior to first dose of study treatment
12. Concomitant use of known strong (eg. phenobarbital, enzalutamide,
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine
and St John's Wort) or moderate CYP3A inducers (eg. bosentan,
efavirenz, modafinil). The required washout period prior to starting
study treatment is 5 weeks for enzalutamide or phenobarbital and 3
weeks for other agents
13. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer
therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy
14. Major surgery within 2 weeks of starting study treatment: patients
must have recovered from any effects of any major surgery
15. Immunocompromised patients, eg, patients who are known to be
serologically positive for human immunodeficiency virus (HIV)
16. Patients with known active hepatitis (ie, hepatitis B or C)
Please see protocol for further details |
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E.5 End points |
E.5.1 | Primary end point(s) |
Study end points are defined for the following patient populations: BRCAm, Non BRCAm HRRm, Non HRRm
- PFS using BICR according to RECIST 1.1
- Sensitivity analysis of PFS using Investigator assessments according to RECIST 1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Study end points are defined per the patient populations
- PFS and objective response using BICR according to RECIST 1.1
- Sensitivity analysis of PFS and objective response using Investigator assessments according to RECIST 1.1
- DoR and tumour change using BICR according to RECIST 1.1
- Sensitivity analysis of DoR, and tumour change using Investigator assessments according to RECIST 1.1
- Time to death for any cause
- Mutation status of HRR pathway genes
- Cmin ss
Safety
- AEs (severity graded by CTCAE v4)
- laboratory tests (clinical chemistry, haematology and urinalysis)
- vital signs (pulse and BP)
- ECG data
- ECOG PS |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 117 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Korea, Republic of |
Taiwan |
United States |
Belgium |
France |
Germany |
Ireland |
Italy |
Netherlands |
Poland |
Portugal |
Spain |
United Kingdom |
Czechia |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |